Currently known anticancer agents include anticancer DDS agents using antibodies against tumor cells as a targeting carrier. However, this type of anticancer agent has the disadvantage that tumor interstitial pressure or other barriers hinder permeation of the agent to significantly lower the performance of drug delivery to the target. Moreover, a particular antibody could not be used as a common targeting carrier for various types of tumors, because of heterogeneity of antigens on the surface of tumor cells.
However, there may be expressed common specific molecules in tumor tissue vessel endothelial cells (TEC) irrespective of the type of cancer because tumor vessels have many common characteristics such as enhanced permeation function. Targeting therapy directed to tumor vessels is expected to effectively achieve the advantages of anticancer DDS agents without concern about barriers to transfer to tissues, and therefore, monoclonal antibodies which are specific for vessel endothelial cells, particularly vessel endothelial cells existing in tumor tissues (tumor vessel endothelial cells) have been developed.
Up to the present, markers widely recognizing vessel endothelial cells such as CD31, CD36, Ulex europaeus-I agglutinin (UEA-1) and markers generally expressed inactivated large vessel endothelial cells such as von Willebrand factor (vWF), ICAM-1 (CD54), E-selectin have been known.
On the other hand, tumor vessel endothelial cells are postulated to express specific antigens which are not expressed in normal tissues as described above, and various antibodies recognizing tumor vessel endothelial cells have been reported up to the present, among which some examples are listed below:    E-9 antibody (Wang, J. M. et al., Int. J. Cancer (1993) 54, 363);    anti-FB5 (endosialin) antibody (Rettig, W. J. Pro. Natl. Sci. USA (1992) 89, 10832);    H4/18 antibody (Cotran, R. S. et al., J. Exp. Med. (1986) 164, 661);    Q BEND/10 antibody (Ramani, P. et al., Histopathology (1990) 17, 237);    EN4/EN3 antibody (Schlingemann, R. O. et al., Amer. J. Pathol. (1991) 138, 1335);    BMA120 antibody (Schlingemann, R. O. et al., Amer. J. Pathol. (1991) 138, 1335);    EN7/44 antibody (Hagemeier, H. H. et al., Int. J. Cancer (1986) 38, 481);    PAL-E antibody (Schlingemann, R. O. et al., Amer. J. Pathol. (1991) 138, 1335);    HEC-1 antibody (Gougos, A. et al., J. Immunol. (1988) 141, 1934);    TEC4 and TEC11 antibodies (Thorpe, P. E. et al., Am. Assoc. Cancer Res. (abstract) (1994) 35, 379).
However, antigens recognized by these antibodies are also expressed in normal endothelial cells or other cell species, though in a minor amount, and nothing has been reported about antitumor effects of these antibodies, leading to a demand for development of antibodies which are more suitable for the therapy of solid cancers targeting tumor vessel endothelial cells.
CD 44 is a known antigenic protein existing on the surface of lymphocytes or the like (J. Immunol., 142, 2045–2051, Mar. 15, 1989), and monoclonal antibodies against CD44 have been reported (JP Laid-open Publication (Kokai) No. 508309/93; WO94/12631; and WO95/33771). However, these antibodies against CD44 have not been reported to recognize antigens on the surface of tumor vessel endothelial cells, and CD44 has not been reported to exist on the surface of tumor vessel endothelial cells, either, prior to the priority date of the present application.